1. Field of the Invention
The present invention relates to inhibiting antro-duodenal motility with GLP-1 and methods to alleviate discomfort during endoscopy and to alleviate symptoms of gastrointestinal disorders.
2. Description of the Related Art
Glucagon has been widely used to cause a variable reduction in gastroduodenal motility. The effect of glucagon appears to be dose-dependent with a minimally effective dose being 0.5 mg. Glucagon, however, does not facilitate colonoscopic evaluation (Norfleet, Gastrointest. Endosc., 24, 164-5, 1978), and at doses as high as 2 mg glucagon does not reduce contractions in the antrum (Gregerson et al., Scand. J. Gastroenterol. 23 (Supp 152), 42-47 (1988)). Furthermore, glucagon is contraindicated in persons with diabetes (Paul and Freyschmidt, ROFO Rortschr. Geb. Rontgenstr. Nuklearmed., 125, 31-7 (1996)), is expensive and its efficacy has been questioned.
Side effects associated with the use of glucagon include nausea and vomiting. The effects are dose-dependent and can appear at a dose of 1 mg (Larsen et al., Scand. J. Gastroenterol. 21, 634-640, 1986; Gregersen et al., supra, Diamant Handbook Experimental Pharm, Lefevre ed., Vol. 66/2, 611-643, 1983). As dosages required to sufficiently reduce motility frequently exceed 1 mg, side effects from glucagon use are common. Such side effects render the patient extremely uncomfortable and often cause the endoscopic procedure to be interrupted or aborted.
Hyoscamine sulfate has antispasmodic activity and been used for treatment of irritable bowel syndrome and also has adverse side effects (Lahoti et al., Gastrointest. Endosc. 46, 139-142 (1997)). Otreocide, a somatostatin analog, has also been used and proven effective in treating clinically significant diarrhea during rapid detoxification and postoperative dumping syndrome, but is associated with an unacceptable incidence of bradycardia; its long-term use is limited by side effects.
The proglucagon-derived glucagon-like peptide-1(7-36)amide (GLP-1) is a gastrointestinal hormone that is released postprandially from the L-cells of the gut (Gxc3x6ke et al., Eur. J. Clin. Invest. 21, 135-44 (1991); Schirra et al., J. Clin. Invest. 97, 92-103 (1996)). Previous studies in humans have shown synthetic GLP-1 to substantially retard gastric emptying of liquid and solid meals (Schirra et al., J. Endocrinol, 156, 177-86 (1998); Wettergren et al., Dig. Dis. Sci. 38, 665-673 (1993); Schirra et al., Proc. Assoc. Am. Physicians 109, 84-97 (1997)). Transpyloric pulsatile flow regulated by the motility of the antro-pyloro-duodenal region is a major mechanism of gastric emptying (Malbert and Mathis, Gastroenterol. 107, 37-46 (1994); Anvari et al., J. Physiol. (London) 488, 193-202 (1995)). Antral contractions, and especially antro-duodenal coordinated ones, were shown to be associated with the gastric emptying rate of liquids (Schirra et al., J. Clin. Invest. 97, 92-103 (1996); Camilleri et al., Am J Physiol 249, G580-585 (1985); Houghton et al., Gastroenterol. 94, 1276-84 (1988)) and solids (Fraser et al., Am. J. Physiol. 264, G195-201 (1993)). Tonic and localized phasic pressure increases generated by the pylorus provide an important braking mechanism, diminishing gastric outflow (Anvari et al., J. Physiol. (London) 488, 193-202 (1995); Heddle et al., Dig. Dis. Sci. 38, 856-69 (1993); Heddle et al., Gut 29, 1349-57 (1988); Tougas et al., Gut 33, 466-471 (1992)).
It is therefore an object of the present invention to provide a method for inhibiting antro-duodenal motility with an effective, therapeutic composition that has minimal side effects. It is well known that GLP-1 does not cause hypoglycemiaxe2x80x94and it did not cause hypoglycemia during the experiments discussed in the present application, nor did it cause any other side effects. Accordingly, a dosage unit comprising a GLP-1 molecule and a pharmaceutically suitable excipient is also disclosed.
In a related vein, the present invention also encompasses a method for premedicating in endoscopic procedures, comprising administering a GLP-1 molecule prior to or during an endoscopic procedure.
Another embodiment of the present invention is a method for treating or preventing gastrointestinal disorders, including but not limited to, irritable bowel syndrome, non-infectious acute and chronic diarrhea and post-operative dumping syndrome, that comprises administering to the patient therapeutically effective amount of a GLP-1 molecule.
Further encompassed by this invention is a method for treating or preventing symptoms associated with narcotics withdrawal, by administering a GLP-1 molecule as described above.
In another embodiment, the invention includes a method for inhibiting pyloric motility in a patient in need thereof that comprises administering to the patient a therapeutically effective amount of an antagonist to a GLP-1 molecule.